MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Many individuals with autism spectrum disorder (ASD) have gastrointestinal problems, such as constipation, irritable bowel syndrome and abdominal pain, but the cause of these GI issues is not currently known. Previous research from our laboratory showed a significant positive relationship between cortisol levels and GI problems, especially for constipation. However, it is possible that other factors such as diet may affect GI functioning, especially since many children have altered diets. This study examined 32 different nutrients in the children’s diets, as assessed by a food frequency questionnaire that assessed the participant’s diet over the past month, and how each nutrient was related to upper and lower GI tract symptom scores over the past month created from the Questionnaire on Pediatric Gastrointestinal Symptoms – Rome III. The results showed no significant relationships between any of the nutrients and GI symptoms, suggesting that diet was not associated with GI symptoms in this sample.

Joseph Piven, MD
The Thomas E. Castelloe Distinguished Professor of Psychiatry
UNC School of Medicine
Director of the Carolina Institute for Developmental Disabilities
Co-senior author of the study

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Babies with older siblings with autism are at an increased risk (20%) of getting autism over the general population (1%). Infants who later are diagnosed with autism don’t have any of the stigmata of autism in the first year of life. The symptoms of autism unfold in the first and particularly in the second year of life and beyond.

We have evidence to support the idea that behavioral symptoms of autism arise from changes in the brain that occur very early in life. So we have employed MRI and computer analyses to study those early brain changes and abnormalities in infancy to see if early brain changes at 6 months of age can predict whether babies at high-risk of developing autism will indeed develop the condition at age two.

For this particular study, we used data from MRIs of six-month olds to show the pattern of synchronization or connection across brain regions throughout the brain and then predict which babies at high familial risk of developing autism would be most likely to be diagnosed with the condition at age two.

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Autism has both genetic and environmental risk factors. Our aim was to study if exposure to toxic metals, such as lead, or disruptions in the uptake of essential nutrient elements such as manganese or zinc would be related to autism risk. Furthermore, we were interested in not only understanding how much exposure had taken place but also which developmental periods were associated with increased susceptibility to autism risk.

Researchers suspect that the risk factors for autism start early in life, even prenatally, but measuring in utero exposures is technically very challenging. We used a newly developed technique that uses lasers to map growth rings in baby teeth (like growth rings in trees) to reconstruct the history of toxic metal and essential nutrient uptake. We applied this technology in samples collected from twins, including twins who were discordant for autism. This allowed us to have some control over genetic factors.

We found that twins with autism had higher levels of lead in their teeth compared to their unaffected twin siblings. They also had lower levels of zinc and manganese. The lower uptake of zinc was restricted to approximately 10 weeks before birth to a few weeks after birth, indicating that as a critical developmental period.

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: A 22q11.2 deletion confers the highest known genetic risk for schizophrenia, but a duplication in the same region is strongly associated with autism and is less common in schizophrenia cases than in the general population.

Thus, we became interested in trying to understand whether there were differences in brain development that might predispose to one condition vs. the other.

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Fragile X syndrome (FXS) is a neurodevelopmental disorder characterized by cognitive impairment and affects 1 in 4000 males and 1 in 6000 females. About 60% of persons with Fragile X also have autism spectrum disorder. FXS is caused by absence of Fragile X protein (FMRP), which results in hyperactivation of ERK (extracellular signal-regulated kinase) and mTORC1 (mechanistic target of rapamycin complex 1) signaling. We show that treatment with metformin, the most widely used FDA-approved antidiabetic drug, suppresses translation by inhibiting the ERK pathway, and alleviates a variety of behavioural deficits, including impaired social interaction and excessive grooming. In addition, metformin also reversed defects in dendritic spine morphogenesis and synaptic transmission.Continue reading →

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Depression is one of the most common problems that can complicate a pregnancy. Untreated, or incompletely treated, it can be associated with significant harm to mother and child. While psychotherapies alone may be effective for women with mild (or even moderate) severity symptoms, sometimes antidepressant medication is required. In these cases, the benefits of treatment must be weighed against potential risks. Previous research suggested that there may be an increased risk for autism in children exposed to antidepressant medication during pregnancy. However, previous studies were limited in their ability to account for other potential causes of autism in their analyses. In our study, we used several different strategies to try to compare children whose pregnancy exposures were very similar, except for exposure to an antidepressant.

The main finding was that after using these strategies, there was no longer a statistically significant association between in-utero antidepressant exposure and autism.

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Results from recent studies have suggested an increased risk for Autism Spectrum Disorders (ASDs) in children exposed to antidepressants in utero.

We performed a systematic review of and a meta-analysis of published studies to assess the association between ASDs and fetal exposure to antidepressants during pregnancy for each trimester of pregnancy and preconception.

Our systematic review and meta-analysis suggests a significant association between increased ASD risk and maternal use of antidepressants during pregnancy; however, it appears to be more consistent during the preconception period than during each trimester. In addition, the association was weaker when controlled for past maternal mental illness. Maternal psychiatric disorders in treatment before pregnancy rather than antenatal exposure to antidepressants could have a major role in the risk for Autism Spectrum Disorders.

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: The research letter discusses the possible link between rainfall precipitation and risk of autism. Earlier research suggested a link, although there remained quite a bit of skepticism surrounding the findings at the time.

The purpose of the study was to briefly highlight the role of environmental exposure to the agricultural and combustion pollutant, nitrous oxide (N2O), as a possible etiological factor in neurodevelopmental disorders. We have published a series of epidemiological investigations, reviews, and correspondences discussing this possibility. In my continued research on this topic, I learned that rainfall and extreme weather-related events, like hurricanes, drive N2O emissions, especially from nitrogen amended soils. Exposure to this particular air pollutant may, therefore, plausibly undergird the relationship between rainfall precipitation and risk of autism.

Guodong Liu, PhD
Assistant Professor
Division of Health Services and Behavioral Research
Department of Public Health Sciences, A210
Penn State University College of Medicine
Hershey, PA 17033

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Adolescents with autism spectrum disorder (ASD) use emergency department services four times as often as their peers without autism, according to Penn State College of Medicine researchers. The findings suggest that youth with autism may need better access to primary care and specialist services.

MedicalResearch.com: What should readers take away from your report?

Response: Although there was no significant increase in autism rates among adolescents in the study over the nine-year period, emergency department use in adolescents with autism increased five-fold, from 3 percent in 2005 to 16 percent in 2013. During the same time period, emergency department use in adolescents without an autism diagnosis remained steady at around 3 percent. there could be a link between this underutilization of preventive care services and overuse of emergency department services.

On average, adolescents with autism had a four-time higher risk of visiting the emergency department than adolescents without ASD. Older adolescents with autism also visited the emergency department more often than their younger counterparts. A third of middle and late adolescents in this group had medical emergencies, compared to just one-tenth of early adolescents. Females and individuals living in rural areas were more likely to visit the emergency room than males and those living in urban areas.

MedicalResearch.com: What recommendations do you have for future research as a result of this study?

Response: We want to see more data on adolescents with ASD to confirm his findings. We are planning a similar study of emergency department use in adolescent Medicaid patients with autism. Our goal is to plot an unbiased nationally representative picture of how this special population fares in terms of their emergency department usage and, in related work, hospitalizations.

We are also searching for modifiable factors that could be addressed to reduce emergency visits and resulting hospitalizations in adolescents with autism.

MedicalResearch.com: Is there anything else you would like to add?

Response: These Young ASD patients need to be actively taken care of and monitored. There should be better communication between these adolescents and their caregivers and with their regular pediatricians and specialists. If we can do those kinds of things we may help them have less frequent emergencies. This study was published by the Journal of Autism and Developmental Disorders.

I have no disclosures.

Lead author: Dr. Guodong Liu, assistant professor of public health sciences, Penn State University College of Medicine.

Other researchers on this study were Amanda M. Pearl, PhD and Michael J. Murray, MD, Department of Psychiatry; Lan Kong, PhD, Division of Biostatistics and Bioinformatics, Department of Public Health Sciences; and Douglas L. Leslie, PhD, Division of Health Services and Behavioral Research, Department of Public Health Sciences, all at Penn State College of Medicine.

Penn State College of Medicine Junior Faculty Development Program funded this research.

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: The prevalence of autism has been increasing especially in the past two decades. With an estimate of more than 3.5 million people living with autism in the US, approximately 500,000 of them are children under 15 years old. Current studies show that males are approximately four times as likely than females to be diagnosed with autism. There is also evidence that people with autism are at a heightened risk of injury. However, the research on the relationship between autism and injury is understudied.

We found that 28% of deaths in individuals with autism were due to injury, compared to 7% of deaths in the general population. Injury deaths in individuals with autism occurred at a much younger age (29.1 years) on average compared to injury deaths in the general population (54.7 years). Our study show that drowning was the leading cause of injury death among individuals with autism, followed by suffocation and asphyxiation. Children under the age of 15 years were 160 times more likely to die from drowning.

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Autism Spectrum Disorders (ASD) refers to complex neurodevelopmental disorders arising from the interaction of genes and environmental factors. There are no defined mechanisms explaining how environmental triggers can lead to these conditions. One hypothesis based on the gut-brain axis connection suggests that inappropriate antigens trafficking through an impaired intestinal barrier, followed by passage of these antigens through a permissive blood-brain barrier (BBB), can be part of the chain of events leading to the disease.

Many Autism Spectrum Disorders children experience co-morbid medical conditions, including gastrointestinal (GI) dysfunctions whose underlying nature is poorly understood. Several clinical observations describe increased intestinal permeability in ASD with often conflicting findings. Permeability to neuroactive food antigens derived from the partial digestion of wheat (gliadorphins) and cow’s milk (casomorphins) has been reported in ASD. However, while evidence of a permeable gut barrier in ASD is increasingly reported, no information is available concerning a similar breach for the BBB. The BBB is a critical line of defense in the Central Nervous System, limiting the access of circulating solutes, macromolecules, and cells that could negatively impact neuronal activity. Dysfunctions of the BBB have been associated with numerous inflammatory neurologic disorders, such as stroke, epilepsy, multiple sclerosis, Parkinson’s and Alzheimer’s disease.

David Q. Beversdor MD
Center for Translational Neuroscience
University Hospital
University of Missouri Health System
Columbia, MO 65212

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Altered stress reactivity, alterations in cytokines and a high incidence of gastrointestinal disturbances have all been observed in autism spectrum disorder (ASD). We wished to examine the interactions between these factors.

What we found was that patients with greater stress reactivity, as indicated by cortisol response in the testing environment, had greater symptomatology involving the lower gastrointestinal tract, which was predominated by constipation.

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: People with autism and with schizophrenia both have problems interacting and communicating with other people, because they cannot easily initiate social interactions or give appropriate responses in return. On the other hand, the disorders of autism and schizophrenia develop in very different ways. The first signs of Autism Spectrum Disorder (ASD) typically occur during infancy or early childhood, whereas the symptoms of schizophrenia usually do not appear until early adulthood. The researchers asked whether it is possible to disentangle the apparent symptom overlap in ASD and schizophrenia through genetic analyses.

As clinical diagnoses relate to the age of onset of a disorder and do not capture multiple developmental stages, the researchers used a trick. They assumed that there is a continuum between normal and abnormal behaviour and captured social communicative competence – the ability to socially engage with other people successfully – in participants of a population-based birth cohort during development.

Specifically, the researchers studied the genetic overlap between the risk of having these psychiatric disorders and these measures of social communicative competence. Investigating thousands of genetic variants with small effects across the genome, they showed that genes influencing social communication problems during childhood overlap with genes conferring risk for autism, but that this relationship wanes during adolescence. In contrast, genes influencing risk for schizophrenia were most strongly interrelated with genes affecting social competence during later adolescence, in line with the natural history of the disorder.

“The findings suggest that the risk of developing these contrasting psychiatric conditions is strongly related to distinct sets of genes, both of which influence social communication skills, but exert their maximum influence during different periods of development”, explained Beate St Pourcain, senior investigator at the Max Planck Institute and lead author of the study. This is consistent with studies showing that genetic factors underlying social communication behaviour also change to some degree during childhood and adolescence.

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: These results help clarify an important and longstanding question in autism: why do children with autism look less at other people’s eyes?

Two ideas for reduced eye contact in autism have been proposed:
– One idea is that children with autism avoid eye contact because they find it stressful and negative.
– The other idea is that children with autism look less at other people’s eyes because the social cues from the eyes are not perceived as particularly meaningful or important.

This study is important because each idea reflects a very different understanding of what autism is. And maybe even more importantly, each idea reflects a very different view about the right treatment approach to autism and to reduced eye contact in autism.

To answer this question, we used eye-tracking technology to study how 86 children with and without autism paid attention to other people’s eyes.

Children were tested when they were just two years old, at their time of initial diagnosis.

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Studies have shown that accessing intensive behavioral intervention (IBI) services at younger ages is associated with improved outcomes for children with autism spectrum disorder (ASD). In Ontario, Canada, children wait years to access publicly-funded IBI. This analysis estimated costs and projected adult independence for three IBI wait time scenarios: the current wait time, a wait time reduced by half, and an eliminated wait time. The model inputs came from published literature.

The main findings showed that eliminating the wait time generated the most independence and cost the least amount of money to both the government and society. With no wait time for intensive behavioral intervention, the government would save $53,000 (2015 Canadian dollars per person) with autism spectrum disorder over their lifetime, and society would save $267,000 (2015 Canadian dollars).

MedicalResearch.com: What is the background for this study? What are the main findings

Response: Gender dysphoria or transgenderism (GD) and autism spectrum disorders (ASD) often co-occur. Between 9 and 25% of youth referred for gender dysphoria concerns have co-occurring ASD. Autistic transgender youth often require significant supports; their autism symptoms alone present challenges, but when combined with gender dysphoria, the clinical needs and complexities increase significantly. For example, an autism spectrum disorder, with its resulting social and communication challenges, can make it more difficult for a transgender teen to advocate for their needs around gender. Specialists from youth gender clinics from around the world have years of experience working with autistic transgender youth. This study used an international search process to identify experts in co-occurring ASD and GD. Twenty-two experts were identified and participated in this multi-stage consensus building study. A set of initial clinical guidelines for the evaluation and care of youth with co-occurring ASD and GD were produced.

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: The study is a follow-up of a treatment trial on which we have previous reported. In the original Preschool Autism Communication Trial (PACT), 152 children aged 2-4 with autism were randomised to receive the 12 month early intervention or treatment as usual. The type of early intervention used in this study focuses specifically on working with parents. Through watching videos of themselves interacting with their child and receiving feedback from therapists, parents are able to enhance their awareness and response to their child’s unusual patterns of communication; they become better able to understand their child and communicate back appropriately in a focused way. Parents take part in 12 therapy sessions over 6 months, followed by monthly support sessions for the next 6 months. In addition, parents agree to do 20-30 minutes per day of planned communication and play activities with the child.

The study published today is the follow-up analysis of the same children approximately 6 years after the end of treatment. The main findings are that children who had received the PACT intervention aged 2-4 had less severe overall symptoms six years later, compared to children who only received ’treatment as usual’ (TAU) with improved social communication and reduced repetitive behaviours, although no changes were seen in other areas such as language or anxiety. These findings on an international recognised and blind rated observational measure of autism symptoms were accompanied by improvements in children’s communication with their parents for the intervention group, but no differences in the language scores of children. Additionally, parents in the intervention group reported improvements in peer relationships, social communication and repetitive behaviours. However, there was no significant difference between the two groups on measures of child anxiety, challenging behaviours (eg, conduct/oppositional disorder) or depression.

Response: Several years ago, Laurent Fasano discovered that the Drosophila teashirt gene was needed to pattern the body of embryonic flies.

He then found that this transcription factor had three similar genes in mammals.

Working with Adrian Woolf in the UK, they found that Teashirt-3 (Tshz3) was needed in mice to make muscle form in the ureter When the gene was mutated, mice were born with ureters that were ‘blown-up’ and they failed to milk urine from the kidney with the bladder.

Response: Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders which affect about 1 in 68 children in the United States, according to data from the Centers for Disease Control and Prevention. Brain-derived neurotrophic factor (BDNF) is an important moderator in neurodevelopment and neuroplasticity, and studies have suggested the involvement of BDNF in ASD. Although some clinical studies show abnormal expression of BDNF in children with ASD, findings have been inconsistent. Therefore, we undertook a systematic review of the scientific literature, using a meta-analysis to quantitatively summarize clinical data on blood BDNF levels in children with ASD, compared with healthy peers.

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Researchers from Holland Bloorview Kids Rehabilitation Hospital / University of Toronto (Canada), Ohio State University, University of Pittsburgh, Columbia University, and Vanderbilt University, led a double-blind, placebo-controlled randomized clinical trial to examine whether metformin, a common type-2 diabetes drug, may be effective in counteracting weight gain commonly seen with the use of atypical antipsychotic medications, indicated by the FDA for the treatment of irritability in children and youth with autism spectrum disorder (ASD).

Results showed that metformin was effective in helping overweight children and adolescents with autism spectrum disorder (ASD) who take antipsychotic medications lower their body mass index (BMI).

Both FDA-approved antipsychotic medications for treating irritability and agitation symptoms in children and adolescents with ASD can cause a significant increase in weight gain, which in addition to increasing BMI, enhances long-term risk of diabetes. This complicates an already challenging issue as adolescents with autism spectrum disorder are ~ two times more likely to be obese than adolescents without developmental disabilities. Findings of this research are important, especially for families of children with ASD, as managing long-term physical health while also treating irritability/agitation symptoms, can help ensure that their child can participate fully in life (school, etc.).

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Our laboratory is interested in the causes and consequences of the unusual repeat expansion mutation that causes the Fragile X-related disorders. However these disorders are challenging to study, in part because the repeat tract is difficult to amplify by PCR. This makes monitoring of repeat length, as well as other factors we are interested in such as methylation status and the presence of AGG interruptions, quite difficult.

In our experience, both repeat number and methylation status are very variable in patient stem cells and in disease-relevant cell types derived from them. This variability arises because the repeat is prone to both expansion and contraction and because at different times there can be selection for smaller alleles or against unmethylated ones. Thus the frequent monitoring of repeat length and methylation status is critical for work with patient cells, particularly when those cells are to be used for drug screening or to examine the consequences of expansion.

While other assays are available to determine one or more of these parameters, some are cumbersome to use or lack the necessary robustness and sensitivity, whilst others are prohibitively expensive for routine laboratory work. We thus saw a need for assays that are robust, sensitive and cost-effective for preclinical studies.

Response: Acetaminophen (paracetamol) is used by around half of all pregnant women in developed countries and is currently the recommended treatment for fever and pain during gestation. However, evidence linking exposure to this medication with negative changes in neurodevelopment has been coming to light, warranting further study. Therefore, our objective was to evaluate whether prenatal exposure to acetaminophen was adversely associated with child neurodevelopment at 1 and 5 years of age. For this reason, we evaluated 2644 mother-child pairs recruited during pregnancy as part of the INfancia y Medio Ambiente – Childhood and Environment (INMA) project, a Spanish general population-based cohort. We collected information on acetaminophen use prospectively up until week 32 of gestation. We evaluated neurodevelopment at 1 year of age using the Bayley Scales of Infant Development. At 5 years of age we applied a battery of tests evaluating different aspects of neurodevelopment including both cognitive and behavioural aspects.

MedicalResearch.com Interview with:David Beversdorf, M.D.
Associate professor in the departments of radiology, neurology and psychological sciences
University of Missouri and
Missouri University Thompson Center for Autism and Neurodevelopmental Disorders

MedicalResearch.com: What is the background for this study? What are the main findings?

Dr. Beversdorf: Our previous work had demonstrated in retrospective surveys a higher incidence of prenatal psychosocial stress exposure during the late 2nd and early 3rd trimester in pregnancies where the offspring had developed autism spectrum disorder (ASD). This had been confirmed in other studies, including a study examining the timing of exposure to tropical storms during pregnancy. However, not everyone exposed to stress during pregnancy has a child with ASD, so we began to look at genetic risk for augmented stress reactivity. This initial exploration involved examination of the interaction between stress exposure during ASD-associated pregnancies and the maternal presence of variations in one gene well known to affect stress reactivity. Variations in this gene were also targeted as they have been associated with ASD in some studies. We found in two independent groups of patients (one in Missouri, one in Ontario, Canada) that maternal presence of at least one copy of the stress-susceptible variant of this gene is associated with the link between maternal stress exposure during this time window of pregnancy and subsequent development of ASD in the offspring.

MedicalResearch.com: What is the background for this study? Response: Prior studies have demonstrated that schizophrenia, bipolar disorder and autism spectrum disorders (ASD) cluster in the families. Little is known about the clustering of other psychiatric and neurodevelopmental disorders among siblings of probands with ASD. It is well known that ASD frequently co-occur with a range of other disorders such as intellectual disability (ID), attention deficit/hyperactivity disorder (ADHD), behavioral disturbances and anxiety disorders. Therefore, it was plausible to hypothesize that siblings of probands with ASD could have an increased risk for several psychiatric and neurodevelopmental disorders.

The data is based on several nationwide registers from Finland. We examined the whole spectrum of psychiatric and neurodevelopmental disorders diagnosed among the siblings. Data included over 3500 probands with autism spectrum disorders who had over 6000 siblings. They were compared to nearly 12 000 controls with over 22 000 siblings. Siblings in this cohort ranged from 4 to 32 years old.

MedicalResearch.com: What are the main findings?

Response: The main finding of the study is that the siblings of the probands with autism spectrum disorders were diagnosed more often with all psychiatric and neurodevelopmental disorders investigated except substance abuse disorders as compared to siblings of controls. Especially childhood onset disorders, including ASD, ADHD, ID, childhood emotional disorders, learning and coordination disorders, conduct and oppositional disorders and tic disorders were more frequent among siblings of ASD probands.

MedicalResearch.com: What should clinicians and patients take away from your report?

Response: It is important to notice that these findings were observed in the population level. Therefore, these findings cannot be applied to determine the risk for disorders of a single child. However, clinicians working with the families of individuals with autism spectrum disorders should pay particular attention to the siblings of proband for early recognition and rehabilitation. For example, it has been shown that early recognition and diagnosis of ASD and fast referral to rehabilitation are important predictors of the prognosis of autism spectrum disorders.

MedicalResearch.com: What recommendations do you have for future research as a result of this study?

Response: There was an unequal time of follow-up of siblings, with the youngest siblings being followed only for four years. Future research on this topic should have a longer period of follow-up for the whole cohort. In addition, it would be important to evaluate the specific environmental factors associated with these disorders together with the genetic studies searching for shared genotypes.

MedicalResearch.com: What is the background for this study? What are the main findings?

Dr. Hicks: This research was inspired by results of the CHARGE study (examining environmental influences on autism) which showed that specific pesticides (including pyrethroids) increased the risk of autism and developmental delay, particularly when mothers were exposed in the 3rdtrimester.

We recognized that the department of health sprayed pyrethroids from airplanes in a specific area near our regional medical center every summer to combat mosquito borne illnesses. We asked whether children from those areas had increased rates of autism and developmental delay. We found that they were about 25% more likely to be diagnosed with a developmental disorder at our medical center than children from control regions without aerial spraying of pyrethroids.

Dr. Ya Wen: At the time of this study (December 2014), the SFARI (Simons Foundation Autism Research Initiative) Gene-Human Gene Module recorded 667 human genes implicated as relevant to Autism spectrum disorders (ASDs). Now the number is close to 800. We sought to address the challenge of making sense of this large list of genes by identifying coherent underlying biological mechanisms that link groups of these genes together. To do this, we used information from several existing and well established databases and created a “demographics” of autism genes and pathways.

MedicalResearch.com: What are the main findings?

Dr. Ya Wen: From these hundreds of autism genes, we first found the relatively most important pathways, and then we generated a pathway network by mapping the pathway-pathway interactions into an Autism Pathway Network. Our systems analyses of this network converged upon an important role in autism pathophysiology for two pathways: MAPK signaling and calcium signaling, and specifically the process where they overlap, “calcium-protein kinase C-Ras-Raf-MAPK/ERK”. Our study also illuminated genetic relationships between autism and several other kinds of illness, including cancer, metabolic and heart diseases. Many of the significant genes and pathways were associated with vulnerability in the processing of challenging environmental influences.

MedicalResearch.com: What is the background for this study? What are the main findings?

Dr. Charlton: Although Autism Spectrum Disorders are classified as developmental disorders, they last throughout life. Autism Spectrum Disorders were first identified in the 1940s, but it was only from the 1960s onwards that awareness of the condition began to increase. Initial research into Autism focused on the area of greatest need, i.e. childhood and education. Only now that those individuals first diagnosed with Autism are reaching old age are studies able to examine what happens in late-life. Although there are an increasing number of older adults with a diagnosis of Autism Spectrum Disorders, it is often difficult to identify individuals willing to participate in research. One alternative is to explore Autism traits in the general population, this is known as the Broad Autism Phenotype (BAP). These BAP traits occur in relatives of those with Autism and in the general population. By examining the BAP in community-dwelling older adults, we can begin to understand whether these traits confer additional risk to in ageing.

MedicalResearch.com: What did you do in the study? What are the main findings?Dr. Charlton: Adults aged over 60 years old were recruited to take part in the study. They completed questionnaires reporting on presences of Broad Autism Phenotype traits, executive functions (the ability to plan and organise behaviour), mood (depression and anxiety), and social support.

Of the 66 individuals who participated, 20 individuals reported significant BAP traits – classified as the Broad Autism Phenotype group. Individuals in the BAP group reported more problems with executive functions, higher rates of depression and anxiety, and less social support than those in the non-BAP group. Further analyses demonstrated that having Broad Autism Phenotype traits was the factor that most explained presence of depression and anxiety symptoms among these older adults.

Medical Research: What is the background for this study? What are the main findings?

Dr. Zeng: Autism Spectrum Disorders (ASDs) are a group of highly inheritable behavioural disorders that pose major personal and public health concerns. Patients with ASDs have mild to severe communication difficulties, repetitive behaviour and social challenges. Such disorders significantly challenge an individual’s ability to conduct daily activities and function normally in society. Currently there are very few medication options that effectively treat ASDs. Therefore, there is a need to better understand the biology of that produces Autism Spectrum Disorder symptoms.

In the study, we found how one brain-specific microRNA (miR-128) plays a key role in causing abnormal brain development. MicroRNAs are small molecules that regulate gene expression in the human body to ensure proper cellular functions. Although it was known that miR-128 is misregulated in some patients with autism, what that meant and how it functioned was not known. We showed that miR-128 targets a protein called PCM1 that is critical to the cell division of neural precursor cells (NPCs). NPCs during early brain development have two fates – they either stay as NPCs and undergo self-renewal or become neurons through differentiation. The dysfunctional regulation of PCM1 by misregulated miR-128 impairs brain development, which may underlie brain size changes in people with Autism Spectrum Disorders.

Dr. David Grossman MD MPH
Vice chair of the U.S. Preventive Services Task Force
Professor at the University of Washington Schools of Public Health and Medicine

Medical Research: What is the background for this study? What are the main findings?

Dr. Grossman: The Task Force cares deeply about the challenges that children affected by autism and their families face in getting the care and support they need. This was the first time that we assessed the evidence around screening young children for autism, and our recommendation was informed by a review of the most up-to-date science, which included randomized trials, observational studies, and research from a number of Federal health agencies. We concluded that the current evidence is insufficient to assess the balance of benefits and harms of screening for autism spectrum disorder in children for whom no concerns of autism have been raised by their parents or a clinician. This is an I statement, which is not a recommendation against screening, but a call for more research on screening and treatment in young children who don’t have obvious symptoms. It is important to note that this recommendation will not affect insurance coverage for autism screening, which is currently covered under the Affordable Care Act as a result of the American Academy of Pediatrics’ Bright Futures Guidelines.

Medical Research: What is the background for this study? What are the main findings?

Response: Developmental brain disorders (DBD), such as autism, intellectual disability, and schizophrenia are a group of heterogeneous conditions characterized by deficits that affect multiple functional domains, such as cognition, behavior, communication, and motor skills. Previous studies provide strong evidence of common underlying molecular pathways and shared genetic causes among apparently different DBDs.

Large-scale genomic studies of individuals with developmental brain disorders have found that identifying multiple, independent de novo pathogenic loss-of-function (pLOF) variants in the same gene among unrelated individuals is a powerful statistical approach to reliably identify disease-causing genes. However, genomic data from smaller cohorts and case reports are not routinely pooled with data from larger studies. Moreover, most previous studies have been restricted to cohorts of individuals ascertained based on a single diagnosis (e.g., a study will focus on only individuals with a diagnosis of autism and not consider other genomic data from individuals with a different diagnosis). Therefore, genomic data from individuals across DBD are not being jointly analyzed in search of pLOF variants in the same gene that may help build evidence for a causative role in developmental brain disorders.

In this study, we carried out data mining of previously published data to identify genes related to the DBD phenotype. We expanded the aforementioned method and developed a multilevel data-integration approach, which capitalizes on three genotype-phenotype data sources:
(1) genomic data from structural and sequence pLOF variants,
(2) phenotype data from six apparently distinct DBD (autism, intellectual disability, epilepsy, schizophrenia, bipolar disorder and attention-deficit/hyperactivity disorder), and
(3) data from large scale studies, smaller cohorts, and case reports.

We identified 241 candidate genes for developmental brain disorders, including 17 genes that had not previously been associated with developmental brain disorders.

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